Tracleer Bosentan Tablets

Step Forward with Tracleer

For patients with pulmonary arterial hypertension (PAH, WHO Group I) WHO Class II, III, IV
PathophysiologySigns and SymptomsTherapeutic PathwaysEndothelin in PAH*

Endothelin is an important mediator
in pulmonary arterial hypertension*

Endothelin (ET-1) levels are elevated in plasma and lung tissues of pulmonary arterial hypertension* patients1



 Elevated levels of ET-1 in plasma and lung tissues suggest a pathogenic role for endothelin in PAH*1

Excess ET-1 has diverse effects†2-4

AcuteChronic
InflammationCell proliferation
VascoconstrictionFibrosis
 Inflammation
 Hypertrophy


Effects of ET-1 are mediated by ETA and ETB receptors†1

ETA activity in PAH*ETB activity in PAH*
Cell proliferation5Cell proliferation
Vascoconstriction4Vascoconstriction4
Inflammation6Inflammation6
 Fibrosis7
 Hypertrophy3

†Statements are based on observations reported from in vitro, animal, and human trials. The clinical significance is unknown.

  


*INDICATION
Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital systemic-to-pulmonary shunts (18%).

Considerations for use
Patients with WHO class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO class II patients, which may preclude future use as their disease progresses.

IMPORTANT SAFETY INFORMATION
Because of the risks of liver injury and birth defects, Tracleer may be prescribed and dispensed only through the Tracleer Access Program (T.A.P.), a restricted distribution program, by calling 1-866-228-3546. Only prescribers and pharmacies registered with T.A.P. may prescribe and distribute Tracleer. Tracleer may be dispensed only to patients who are enrolled in and meet all conditions of T.A.P.

Liver injury
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with Tracleer. In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were observed after prolonged treatment. In general, avoid using Tracleer in patients with elevated aminotransferases
(>3 × ULN). Measure liver aminotransferases prior to initiation of treatment and then monthly. Discontinue Tracleer if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 × ULN.

Teratogenicity
Based on animal data, Tracleer is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. To prevent pregnancy, females of childbearing potential must use 2 reliable forms of contraception during treatment and for 1 month after stopping Tracleer unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20-IUS inserted, in which case no other contraception is needed. Monthly pregnancy tests should be obtained.

CONTRAINDICATIONS
Tracleer is contraindicated with cyclosporine A, glyburide, in females who are or may become pregnant, or in patients who are hypersensitive to bosentan or any component of Tracleer.

WARNINGS AND PRECAUTIONS
In clinical trials, Tracleer caused ALT/AST elevations (>3 × ULN) in 11% of patients accompanied by elevated bilirubin in a few cases. The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN) and increases in total bilirubin (≥3 × ULN) is a marker for potential serious liver injury. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid using Tracleer in patients with moderate or severe liver impairment or elevated ALT/AST >3 × ULN.
If clinically significant fluid retention develops, with or without associated weight gain, the cause, such as Tracleer or underlying heart failure, must be determined. Patients may require treatment or Tracleer therapy may need to be discontinued.
Preclinical data and an open-label safety study (N=25) showed a decline in sperm count of ≥50% in 25% of Tracleer-treated patients after 3 or 6 months. After 6 months, sperm count remained in normal range, with no changes in sperm morphology or motility, or hormone levels. Endothelin receptor antagonists such as Tracleer may adversely affect spermatogenesis.
Treatment with Tracleer can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and need for specific treatment.
If signs of pulmonary edema occur, the possibility of associated pulmonary veno-occlusive disease should be considered. Tracleer should be discontinued.

ADVERSE EVENTS
In Tracleer pivotal trials, the most common adverse events occurring more often in Tracleer-treated patients than in patients taking placebo (≥2%) were respiratory tract infection, edema, hypotension, sinusitis, arthralgia, liver function test abnormal, palpitations, and anemia.

Please see full Prescribing Information, including BOXED WARNING about liver injury and pregnancy.

  1. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. February 2011.
  2. Rich S, McLaughlin VV. Pulmonary hypertension. In: Libby P, Bonow RO, Mann DL, Zipes DE, eds. Braunwald's Heart Disease. 2 vols. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1883-1914.
  3. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739.
  4. Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391-415.
  5. Davie N, Haleen SJ, Upton PD, et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med. 2002;165:398-405.
  6. Muller DN, Mervaala EM, Schmidt F, et al. Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension. 2000;36:282-290.
  7. Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res. 1993:27:2125-2129.